medicinalchemistryfandomcom-20200214-history
Digestive system
Intro Orally administired drugs are subjected to the same chemical processes as ingested food. Hence understanding the digestive system is important for improviding drug performance. In order to carry out such a vast array of chemical reactions in a highly compact space, the human body effectively runs the process in set stages corresponding to the various organs of the digestive system. Indeed, each organ possesses its own controlled pH, and an associated battery of enzymes as well as co-enzymes that are activated at this pH but denatured at the next. Ingested food will spend from minutes (mouth) to hours (gut) in a single organ where it is effectively mechanically stirred at 37oC in an enzyme bath at a set pH. After all possible chemical transformations have occurred in that organ, it then moves to the next organ in the digestive tract. Fascinatingly, the associated pH change causes the incoming enzymes to denature thus exposing the partially processed food to a new set of reaction conditions and enabling new chemical transformations to take place. Little wonder that after meandering for 12-48 hours through the 8-9 meter length of the digestive track that most complex chemicals have been metabolised to their constituent building blocks. Since the purpose of eating is not to dispose of food waste but to bring nutrients to our body, these chemical building blocks (amino acids, sugars etc,) are carried to and then stored in appropriate cells in the human body. Corinne KAY (n.d.) ‘ADME – When the Path Matters More than the Destination.’, online Available from: http://learn2.open.ac.uk/pluginfile.php/388971/mod_resource/content/1/Kay_2010.pdf (Accessed 12 May 2012). mouth stomach duodenum gut liver kidneys Mouth amalase (ptyalin) drugs of small molecular weight can cross the membrane of the mouth. e.g. water soluble drugs like Glycerin Trinitrate. There attempts to deliver insulin via sublingual route. Stomach food bolus enters the stomach where chemical digestion takes place. some absorption takes place in the stomach Environment hydrochloric acid gastric juices ph 2. Digestion The hydochloric acid and gastric juices aid in the digestion of and food, and will also apply the drug molecules to the same chemical and physical processes Acid-labile drugs cannot be given orally, as they do not survive the stomache acid environment. Absorption only a limited range of substances are absorbed throughthe stomach lining. glucose simple sugars amino acids some fat soluble substances alcohols are readily absorbed through the stomach water moves freely from the gastric contents into the blood In tracer experiments3 using deuterium oxide, about 60 percent of the isotopic water placed in the stomach is absorbed into the blood in 30 minutes. The net absorption of water from the stomach is small however, because water moves just as easily from the blood across the gastric mucosa to the lumen of the stomach. Interestingly, the absorption of both water and alcohol can be slowed if the stomach contains food, especially fat, probably because gastric emptying is delayed and most water in any situation is absorbed from the jejunum. Corinne KAY (n.d.) ‘ADME – When the Path Matters More than the Destination.’, online Available from: http://learn2.open.ac.uk/pluginfile.php/388971/mod_resource/content/1/Kay_2010.pdf (Accessed 12 May 2012). Solubility Only compounds in solution permeate across the GI membrane. The stomach has ph 2. most drugs are not soluble at ph2 @todo Drugs in ionized form cannot be absorbed through the gut wall. There are Solubility tests for drugs Duodenum Pancreatic juices input into the Duodenum facilitate further chemical digestion considerations for drug design inhibiting pancreatic juices can result in Diarrhoea Hepatic Bile Produced in the Liver 400-800ml per day pH 7.8-8.6 The human liver produces 400-800 ml of hepatic bile each day. The bile (pH 7.8 – 8.6) is then concentrated five-fold and stored in the gallbladder by absorption of water and small electrolytes whilst retaining virtually all of the organic molecules. Next, it is ejected from the gallbladder and flows into the duodenum when food enters the intestine. The main constituents of bile are bile salts, bilirubin, end products of hemoglobin breakdown and electrolytes. Bile salts which are surface active, promote dissolution of lipophilic drugs and lipophilic drug formulations, enteric coatings, and waxy drug matrices. Bile salts may also promote membrane permeability of lipophilic molecules through micelle formation and solubilisation. Corinne KAY (n.d.) ‘ADME – When the Path Matters More than the Destination.’, online Available from: http://learn2.open.ac.uk/pluginfile.php/388971/mod_resource/content/1/Kay_2010.pdf (Accessed 12 May 2012). Bile acids are facial amphipathic, meaning they contain both hydrophobic (lipid soluble) and hydrophilic (water soluble) components. Bile salts associate their hydrophobic side with lipids and their hydrophilic side with water. These emulsified droplets are then organized into many micelles, or small droplets of phospholipid arranged so that the interior is filled with hydrophobic fatty acid tails, which increases overall absorption by helping make large fat globules into smaller particles. In essence, bile greatly increases the surface area of fat, allowing easier digestion by lipases, as well as transport of lipids by suspension in water. Anon (n.d.) ‘Bile - New World Encyclopedia’, online Available from: http://www.newworldencyclopedia.org/entry/Bile (Accessed 13 May 2012). The Gut food exits the duodenum and into the second path of the small intestine, named the jejunum the gut is the main route of entry into the blood circulation for a drug after it has passed the digestive system environment 37' pH 6.4 enzymes: maltase, lactase, intestinal lipase nucleases Peristaltic action pushes food along while mixing it thoroughly. Absorption into blood circulation paracellular route transcellular route Paracellular route molecules leave via the space between the cells limited to small polar molecules electrolytes water Transcellular route Active transport Passive transport Active Transport ATP powered transporters L-dopa uses these transporters Passive Transport the gut is lined with villi and microvilli which increase the intestinal absorptive surface area improvinf the absoorption of nutrients into the lumen passing through a membrane is dependent on the solubility drug needs to be in balance; The transport of a drug through a membrane depends largely on its relative solubilities in water and lipids. If the drug is too water soluble it will not enter the membrane, but if it is too lipid soluble it will enter but not leave the membrane. Good absorption requires that a drug’s hydrophilic-lipophilic nature is in balance. The selection of a suitable carrier can be used to fine tune this balance and consequently improve absorption of the drug. Corinne KAY (n.d.) ‘ADME – When the Path Matters More than the Destination.’, online Available from: http://learn2.open.ac.uk/pluginfile.php/388971/mod_resource/content/1/Kay_2010.pdf (Accessed 12 May 2012). P-gp See main article P-gp. Permeability-glycoprotein is a safety mechanism for preventing toxins entering circulation It causes multi-drug resistence in certain cancers digestion Large intestine cellulose bowel->disposed as feces